The purpose of this proposal is to use mouse models to understand the role of TNFa and its receptors in protection from and exacerbation of SLE. TNFa, a pleiotropic cytokine that can mediate both cell survival and cell death, is an important regulator of physiologic and inflammatory immune responses. TNFa antagonists have a remarkable therapeutic effect in a number of autoimmune diseases including rheumatoid arthritis, ankylosing spondylitis, psoriasis and Crohn's disease but have also been associated with exacerbation of certain autoimmune diseases including SLE multiple sclerosis and other demyelinating diseases. In some mouse models of SLE TNFa is protective in the early stages of disease but is overexpressed in inflamed target organs late in disease. Successful anecdotal use of TNFa blockade has been reported in a small number of patients with refractory SLE nephritis. However autoantibody titers increased in the treated SLE patients, raising the possibility that some features of autoimmunity may be exacerbated by this approach. TNFa is made as a soluble and a membrane protein and can bind to two different receptors with different functions. We propose to study the protective effect of TNFa deficiency or specific TNFR blockade on SLE initiation by analyzing the mechanism of induction of anti-DNA antibodies and disease in SLE prone mice bearing knock-in autoreactive immunoglobulin genes. To understand how TNFa is pathogenic in the setting of nephritis we will use therapeutic TNFa or TNFR blockade for induction of remission or maintenance of remission of SLE nephritis and determine how this alters the inflammatory cascade in the kidney as well as the maintenance of the autoreactive B cell response. Our results should allow us to conclude whether the protective and pathogenic effects of TNFa are mediated by different receptors and may help in the design of more selective TNFa blockers for the treatment of SLE.